The ongoing epidemic of obesity in the United States represents a public health emergency that remains unchecked and without specific therapy. To design specific treatments to prevent and treat obesity, we must first understand the mechanisms that regulate feeding and energy expenditure in order to identify potential therapeutic targets. In this proposal, entitled, Role of the lateral hypothalamic area in leptin action, we will analyze novel leptin-regulated neural pathways in the lateral hypothalamic area (LHA) that likely contribute to body energy homeostasis. We have defined the existence of a novel population of LRb-expressing, leptin-responsive LHA neurons that project locally as well as densely innervating the ventral tegmental area (VTA). We hypothesize that LRb-mediated signaling in the LHA is crucial to the regulation of the VTA and activity of the mesolimbic dopamine system, and thereby for the regulation of feeding and energy balance. We will thus study the regulation of LHA LRb neurons and their role in the regulation of physiology by leptin. We propose the following specific aims: 1. Understand the regulation of LHA LRb neurons. Analyze the regulation of gene expression and activity of LHA LRb neurons, and define the mechanisms by which leptin and other factors mediate this regulation. 2. Define the action of LHA LRb neurons on downstream neurons. Define the downstream target neurons of LHA LRb neurons and the role of LHA LRb neurons in the regulation of these downstream neurons, including the mesolimbic dopamine system. 3. Determine the function of LHA LRb neurons in physiologic leptin action. Examine the physiologic function of LHA LRb neurons by examining energy balance and behavior in animals following a variety of genetic and pharmacologic manipulations directed at these neurons. These studies will enable us to understand the mechanisms by which leptin regulates LHA function, and the mechanisms by which LHA LRb neurons interact with other areas of the CNS in order to contribute to the regulation of feeding and energy balance. This information will in turn lay the groundwork for understanding mechanisms by which LHA-driven feeding may be regulated, which is crucial as we seek to determine the pathogenesis of, and potential therapeutic targets for the ongoing epidemic of obesity. PUBLIC HEALTH RELEVANCE: The ongoing epidemic of obesity in the United States represents a public health emergency that remains unchecked and without specific therapy. To design specific treatments to prevent and treat obesity, we must first understand the mechanisms that regulate feeding and energy expenditure in order to identify potential therapeutic targets. In this proposal, we will analyze novel neural pathways in the brain that likely contribute to body energy homeostasis in order to define these mechanisms and the potential therapeutic targets that they represent. [unreadable] [unreadable] [unreadable]